Sustain release of drugs for a long period of time within a therapeutic range is the most effective drug delivery system as it reduces the patient discomfort and compliance. Biomaterial based approach using microspheres is considered as the most successful in this field. Poly (lactide-co-glycolide) (PLGA) based polymeric microsphere is an ideal candidate for this because of its biocompatibility, degradability, ability to drug encapsulation and sustained drug release properties. PLGA microsphere as a drug carrier is a potential candidate for the application of tissue regeneration. In this review, we thoroughly summarized the potential approach of the PLGA microsphere as a drug delivery system in tissue regeneration. We especially addressed the recent advancement of bone, cartilage and neuron regeneration.